Synthesis, antiretrovirus effects, and phosphorylation kinetics of 3'-isocyano-3'-deoxythymidine and 3'-isocyano-2',3'-dideoxyuridine.
The silylated AzddThd 5 and AzddUrd 6 prepared from 2,3'-anhydronucleoside derivatives 3 and 4 were transformed to formamides 7 and 8 by using the sequence RN3----RN = P(C6H5)----RNHCHO. Formamides 7 and 8 were dehydrated to the protected 3'-isocyano derivatives 9 and 10; deblocking gave 11 and 12. Neither 3'-isocyano-3'-deoxythymidine (11) nor 3'-isocyano-2',3'-dideoxyuridine (12) showed anti-HIV activity at noncytotoxic concentrations. ddThd derivative 11 was considerably more toxic to MT-4 cells than ddUrd derivative 12; it also had a much greater affinity (Ki) for MT-4 cell dThd kinase than ddUrd derivative 12. Both compounds appear to be linear mixed-type inhibitors of MT-4 cell dThd kinase.
Hiebl
J
J
Institut für Organische Chemie der Universität Wien, Austria.
Zbiral
E
E
Balzarini
J
J
De Clercq
E
E
D000963:Antimetabolites / Q000138:chemical synthesis; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D015224:Dideoxynucleosides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D006678:HIV / Q000187:drug effects*; D007700:Kinetics; D010766:Phosphorylation; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects
D000963:Antimetabolites; D000998:Antiviral Agents; D015224:Dideoxynucleosides; C062822:3'-isocyano-3'-deoxythymidine; C062823:3'-isocyano-2',3'-dideoxyuridine; D013937:Thymidine Kinase; D013936:Thymidine